Role of advanced glycation end products and their receptors in diabetes accelerated atherosclerosis

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Diabetes is on the increase in the Western world and with this increase comes the burden of increased complications. One of these is atherosclerosis which leads to heart attacks, strokes and gangrene. In this grant we consider the role of a biochemical reaction where sugar attaches to proteins called advanced glycation and how these advaced glycated proteins (AGEs) interact with specific receptors to promote atherosclerosis. We will use novel animal models overexpressing the receptor RAGE or with deletion of the gene for this receptor. We will investigate if these animals are protected against blood vessel disease when made diabetic and will unravel the mechanisms involved. Furthermore we will investigate novel drugs to block vessel damage in a model of diabetic mice prone to atherosclerosis. One of these interventions will involve giving a free form of the receptor RAGE which will trap the circulating AGEs and prevent them from binding to RAGE in the blood vessel wall. This therpeutic principle has been shown in animals to prevent blood vessel disease in diabetes. We will also feed the sugar-attached proteins (AGEs) to these mice prone to atherosclerosis and to the genetically modified mice to see how these proteins directly influence the vessel wall even if diabetes is not present. These studies will ultimately lead to better treatments to prevent, slow down or reverse blood vessel damage in diabetes.